On October 24, 2024 J INTS BIO, a pioneering biopharmaceutical company, reported that it has unveiled promising interim results from the Phase 1/2 clinical trial of its novel 4th-generation EGFR Tyrosine Kinase Inhibitor (TKI), JIN-A02, aimed at EGFR-mutated non-small cell lung cancer (NSCLC) patients who developed resistance and progressive diseases despite treatments (Press release, J INTS BIO, OCT 24, 2024, View Source [SID1234647384]). The data was presented at this year’s edition of ENA (EORTC-NCI-AACR) (Free EORTC-NCI-AACR Whitepaper) Symposium, held in Barcelona, Spain, from October 23-25, 2024, drawing significant attention from the global oncology community.

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Mutations in the epidermal growth factor receptor (EGFR) is a key driver in the pathogenesis of NSCLC, with 3rd Generation EGFR-TKIs like osimertinib serving as the cornerstone of treatment. Unfortunately, eventually resistance to this treatment will occur, leading to cancer relapse and disease progression. JIN-A02, developed by J INTS BIO, is the 4th-generation EGFR-TKI specifically designed to address this. By targeting both the original mutations and those acquired subsequently as a result of cancer treatments, it offers a therapeutic solution for these patients.

The ongoing Phase 1/2 clinical trial evaluates JIN-A02 in patients with advanced or metastatic NSCLC who have developed resistance and disease progression after 3rd-generation EGFR-TKIs use. The study consist of 3 parts: dose escalation (Part A), dose exploration (Part B), and dose expansion (Part C). The data generated so far in Part A has been encouraging with a good safety profile and early efficacy signals, underscoring JIN-A02’s position as a novel treatment for EGFR-TKI-resistant NSCLC.

J INTS BIO said, "New treatment are urgently needed for lung cancer patients whose disease has worsened or relapsed after treatment with 3rd-generation EGFR-TKI. JIN-A02 is potentially one such treatment option that can bring hope to patients world wide."

Study Design and Interim Results:

To date, the Part A of the study has enrolled 16 patients who received increasing doses of JIN-A02, starting with a low dose of 12.5mg daily to 150 mg daily, with the primary objective of determining the maximum tolerated dose (MTD). This Part also look at safety, pharmacokinetics, and anti-tumor activity as secondary objectives. Doses higher than 150mg are currently being studied in this Part.

Key Interim Findings:

Safety: JIN-A02 demonstrated a very favorable tolerability across all dose levels studied so far, with no dose-limiting toxicities (DLTs) observed up to 150mg daily. There has been no myelosuppression and more importantly, no adverse events commonly associated with EGFR TKI such as rash, diarrhea and cardiotoxicity and this despite tumor reduction already being observed. This is the reason higher doses are being studied.
Efficacy: Tumor control were reported early in this study at lower doses. The first instance occurring at a relative low dose of 50mg. In this cohort, Partial Response of the lung lesions with stable disease in brain metastases was reported. Another Partial Response of the lung lesions was reported in the next cohort of 100mg, in a patient with similar primary EGFR mutation. These findings highlight JIN-A02’s potency as a therapeutic agent, even in patients with progressive diseases and who were heavily treated prior to entering this study.
Central Nervous System (CNS): Of interest is JIN-A02 activity against brain metastases, a potentially fatal complication of progressive lung disease. Reduction in the brain metastases was first reported with JIN-A02 in the 100mg Cohort, although stable disease was reported in the 50mg Cohort. These results points to JIN-A02 not only penetrating the tough Blood-Brain Barrier, but also exerting its anti-tumor effects.
Progression to Subsequent Trial Phases:

Once we have the final doses to be used in Phase 2, the dose-expansion part of the study (Part B) will begin, and two doses will be selected and studied in bigger groups of patient to verify its safety, pharmacokinetics, and anti-tumor activity. Part B is essential for the selection of the final dose level to be used in Phase 2 or Part C of this study.

In this final part (Part C), we will investigate JIN-A02 in specific patient populations who are stratified by EGFR mutation subtypes and the presence of CNS metastases. Part C is critical for generating a bigger dataset on the drug’s therapeutic potential across distinct NSCLC patient groups for regulatory approval purposes.

Implications for Future Therapeutic Development

Professor Byeong Cheol Cho of Severance Hospital’s Division of Medical Oncology, South Korea, commented on the significance of these findings, stating, "JIN-A02’s demonstrated efficacy against both lung and its associated CNS disease underscores its potential as a groundbreaking treatment for patients with EGFR-TKI-resistant NSCLC, including and especially those with brain metastases."

JIN-A02’s ability to effectively target CNS lesions represents a notable advancement and as a 4th generation EGFR-TKI, offers hope for patients with very limited options as a result of progression after 3rd-generation TKIs use.

Next Steps in Clinical Development:

J INTS BIO is fully committed to accelerating the clinical development of JIN-A02. And as the clinical study continues to enroll patients ahead of schedule, JIN-A02, is poised to shape the treatment landscape of NSCLC and to offer hope to lung cancer patients worldwide.

On October 24, 2024 Pierre Fabre Laboratories reported that the first patient has been dosed with PFL-002/VERT-002, a monoclonal antibody acting as a degrader of c-MET, in a phase I/II first-in-human dose-escalation, dose-optimization and dose-expansion trial, for patients with Non-Small Cell Lung Cancer (NSCLC) harbouring MET alterations (Press release, Pierre Fabre, OCT 24, 2024, View Source [SID1234647383]).

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The PFL-002/VERT-002 phase I/II trial is an open label, multi-centre study that aims to assess the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary clinical efficacy of PFL-002/VERT-002, as a monotherapy for patients with MET-dependent tumors, including those emerging with acquired resistance to other treatments.

Non-small cell lung cancer (NSCLC) is the most prevalent form of lung cancer, accounting for approximately 85% of newly diagnosed lung cancer cases, and MET, also known as hepatocyte growth factor receptor (HGFR), is an oncogene driver in subsets of patients suffering from NSCLC.1-4 MET exon 14 skipping mutation and MET amplification are found as primary oncogenic drivers and MET amplification as a resistance mechanism to selected targeted therapies.

"PFL-002/VERT-002 targets a clinically validated oncogenic driver with a unique and differentiated mechanism of action, triggering the degradation of the c-MET oncogene. Thus, it provides the opportunity to test a novel therapeutic approach for patients with MET driven tumors. We are looking forward to collaborating with the investigators participating in the first-in-human trial to assess the safety and efficacy of this new agent." said Francesco Hofmann, Head of Research and Development for Medical Care at Pierre Fabre Laboratories.

On October 24, 2024 Cancer Research UK, one of the world’s largest funders of cancer research, and KisoJi Biotechnology Inc., a company focussed on the discovery and development of antibody therapeutics, reported to have signed a landmark agreement to bring KisoJi’s lead asset, KJ-103, into a first-in-human clinical trial (Press release, Cancer Research UK, OCT 24, 2024, View Source [SID1234647382]). KJ-103 is a naked anti-TROP2 antibody that has been created by KisoJi using its proprietary antibody technology.

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Under the agreement, Cancer Research UK’s Centre for Drug Development (CDD) will sponsor, design and deliver a Phase 1/2a clinical trial of KJ-103, in selected TROP2 expressing solid tumours. KisoJi will supply the antibody for the clinical trial and work with CDD to complete the preclinical package. Cancer Research Horizons, Cancer Research UK’s innovation arm, will manage the commercial relationship.

Unlike antibody drug conjugates (ADCs), KJ-103 does not require a cytotoxic payload but instead functions by recruiting immune cells to kill tumour cells. KJ-103 binds to TROP2 in a location distinct from where current TROP2 ADCs bind. It uses TROP2 as a way of directing macrophage activation and phagocytosis of the tumour cells expressing it, leading to tumour cell death.

KJ-103 may provide an alternative treatment option for TROP2-expressing cancers in which TROP2 ADCs have proven ineffective or are not suitable due to their toxicity profile. Tumour types expressing TROP2 include: colorectal, head and neck, ovarian, breast, bladder and lung cancers.

Lars Erwig, Director of the CDD, said: "We are excited to collaborate with KisoJi to bring KJ-103 into clinical development. This partnership aligns with our mission to explore innovative therapeutic approaches for hard-to-treat cancers. With KJ-103’s unique mechanism of action, which harnesses the body’s immune system without the potential toxicity of a drug conjugate, we hope to offer new treatment options for patients with TROP2-expressing solid tumours."

David Young, co-founder and CEO of KisoJi said: "We are thrilled to be advancing KJ-103 into the clinic in partnership with Cancer Research UK. As the first naked antibody to target TROP2 cancers, KJ-103 is the first of a new wave of antibodies to come from our modernised technology platform that leverages AI grounded in biology to create transformative antibody therapeutics."

On October 24, 2024 Accent Therapeutics, a biopharmaceutical company pioneering novel small molecule targeted cancer therapeutics, reported that the U.S. Food and Drug Administration (FDA) has cleared its Investigational New Drug (IND) application for ATX-559, a first-in-class DHX9 inhibitor (Press release, Accent Therapeutics, OCT 24, 2024, View Source [SID1234647381]). In addition, Accent has established a Clinical Advisory Board (CAB) to help guide the Company’s progress in the clinic.

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The ATX-559 Phase 1/2 trial (NCT06625515) is expected to begin dosing patients with a focus on BRCA1- or BRCA2-deficient breast cancer and patients with MSI-H and/or dMMR solid tumors (including certain patients with colorectal, endometrial, gastric, and other cancers) in the fourth quarter of 2024. The clinical study will evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of ATX-559. For more information on the trial, visit the study page on ClinicalTrials.gov.

"The FDA’s IND clearance is a pivotal moment for Accent Therapeutics, propelling our lead program into the clinical arena. This milestone not only validates our scientifically rigorous approach to identifying innovative targets, but also brings us one step closer to helping cancer patients with significant unmet need," said Jason Sager, M.D., Chief Medical Officer of Accent Therapeutics. "ATX-559 has shown remarkable promise in preclinical studies, and we’re excited to now evaluate its potential to meaningfully improve outcomes for patients facing these challenging malignancies."

As Accent prepares to initiate its first clinical trial, the company has also established a Clinical Advisory Board to guide the advancement of its clinical pipeline. The Clinical Advisory Board consists of renowned clinician-scientists and leaders whose strategic insights and clinical expertise will support the Company’s efforts to advance its mission of creating life-changing therapeutics for patients living with cancer.

The newly formed Clinical Advisory Board includes:

Lillian L. Siu, M.D., FRCPC, medical oncologist, Director of the Phase I Program at Princess Margaret Cancer Centre, Professor of Medicine at the University of Toronto, and President-Elect of the American Association for Cancer Research (AACR) (Free AACR Whitepaper)
Josep Tabernero, M.D., Ph.D., Professor of Medicine, Head of the Medical Oncology Department at the Vall d’Hebron Barcelona Hospital Campus, and Director of the Vall d’Hebron Institute of Oncology (VHIO)
Sam Blackman, M.D., Ph.D., co-founder and Head of Research and Development of Day One Biopharmaceuticals
"We are honored to have such distinguished experts join our Clinical Advisory Board as we advance our programs into the clinic," said Shakti Narayan, Ph.D., J.D., Chief Executive Officer of Accent Therapeutics. "Their experience will be invaluable as we work to bring transformative therapies to patients."

Accent is also on track to advance its second program, targeting KIF18A in chromosomally instable tumors, into the clinic with a Phase 1 trial anticipated to begin in early 2025. This marks an exciting phase of growth for the company as it continues to build on its foundational platform technology to develop innovative cancer therapies.

About ATX-559
ATX-559 is a first-in-class DHX9 inhibitor with the potential to address high unmet need indications not adequately served by existing therapies, such as BRCA-deficient tumors (including breast, ovarian, and others), MSI-H and/or dMMR cancers (including colorectal, endometrial, gastric, and others) and additional undisclosed cancer types representing large patient populations. DHX9 is a DNA/RNA helicase that has been reported to play important roles in replication, transcription, translation, RNA splicing, RNA processing, and maintenance of genomic stability. Inhibition of DHX9 exploits key tumor vulnerabilities, resulting in cancer-specific cell death, and thus this enzyme represents a compelling novel oncology target. Accent retains full worldwide rights to ATX-559 and the DHX9 program.

About KIF18A
Accent’s second lead program is a potential best-in-class inhibitor for KIF18A which may address a large patient population across several cancer indications, including ovarian and triple negative breast cancer (TNBC). KIF18A is a mitotic kinesin motor protein critical for cell division in select tumors with chromosomal instability. A subset of tumor cells with an abnormal number of chromosomes (aneuploid) are reliant on KIF18A and show rapid cell killing in vitro and in vivo upon KIF18A inhibitor treatment, while cells with normal numbers of chromosomes (euploid) are unaffected.

On October 24, 2024 Aktis Oncology, a clinical-stage oncology company focused on unlocking the breakthrough potential of targeted radiopharmaceuticals for large patient populations not addressed by existing platform technologies, reported data presented on its potential first-in-class, Nectin-4 targeting miniprotein radiopharmaceutical, AKY-1189, in three abstracts, including one oral presentation, at the EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium on Molecular Targets and Cancer Therapeutics in Barcelona, Spain, October 23-25, 2024 (Press release, Aktis Oncology, OCT 24, 2024, View Source [SID1234647380]). AKY-1189 is designed to deliver actinium-225 to Nectin-4 expressing tumors, with potential applications in locally advanced or metastatic urothelial carcinoma (mUC) and other Nectin-4 expressing cancers, such as breast, lung, colorectal and cervical.

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Mike Sathekge, MD, Head of Nuclear Medicine Department, University of Pretoria, and Steve Biko Academic Hospital, and President and CEO, Nuclear Medicine Research Infrastructure (NuMeRI), will present an oral plenary on the human biodistribution and dosimetry data of AKY-1189. The plenary presentation (Abstract no. 10), titled "AKY-1189, a novel, first-in-class miniprotein radiopharmaceutical designed to deliver Actinium-225 (225Ac) to Nectin-4 expressing tumors with broad therapeutic applications in metastatic urothelial carcinoma (mUC) and other Nectin-4 expressing tumors," demonstrates a promising profile for AKY-1189 in patients with Nectin-4 expressing tumors. Pursuant to Section 21 guidelines of the South African Health Products Regulatory Authority (SAHPRA), 20 patients diagnosed with mUC, metastatic breast cancer, non-small cell lung cancer carcinoma, colorectal cancer and cervical cancer were imaged with [68Ga]Ga-AKY-1189 to address patient need. The resulting data were later assessed. A total of 15 patients were evaluable for biodistribution and tumor uptake analysis. Eight patients were dosed with [177Lu]Lu-AKY-1189 and were evaluable for kidney and bone marrow dosimetry. The assessment demonstrated AKY-1189 to be generally well tolerated with no treatment-emergent adverse events, and dosimetry analyses suggest a wide therapeutic index for [²²⁵Ac]Ac-AKY-1189. Significant tumor uptake of AKY-1189 was observed across primary and metastatic lesions in multiple cancer types evaluated. These data mark the first Nectin-4 targeted radiopharmaceutical to demonstrate significant tumor uptake and supports the progression of [²²⁵Ac]Ac-AKY-1189 to therapeutic clinical studies across several solid tumor types. The oral presentation is scheduled on Friday, October 25 from 1:12-1:24 p.m. CEST.

"These data provide evidence of sufficient tumor uptake of AKY-1189, not only in mUC but in other tumor types, and that AKY-1189 has promising biodistribution in normal organs and tissues," said Professor Sathekge. "This discovery marks a critical step forward in the fight against Nectin-4 expressing cancers, and sheds light on radiopharmaceuticals as a potential mainstream oncology treatment."

Aktis also showcased AKY-1189’s potential as a targeted radiopharmaceutical through two poster presentations displayed within the Exhibition Hall, which are both available online for viewing. The first poster (Abstract no. 118), titled, "Discovery and pre-clinical development of AKY-1189, a potent and selective Nectin-4 miniprotein binder optimized for use as a targeted radiopharmaceutical," highlighted AKY-1189’s preclinical data supporting advancement to clinical development.

The second poster (Abstract no. 308), titled, "Allometric scaling of preclinical dosimetry for the Nectin-4 miniprotein binders AKY-807 and AKY-1189 accurately predicts human absorbed dose to major organs," highlighted the accuracy of allometric scaling methods in predicting human organ dosimetry from preclinical data.

"The presentations at the EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Meeting underscores the potential of AKY-1189 in targeting Nectin-4 expressing cancers," said Matthew Roden, PhD, President and Chief Executive Officer of Aktis Oncology. "As the first therapeutic product candidate discovered from our novel miniprotein radioconjugate platform, AKY-1189 data suggest that we can achieve a favorable clinical profile and opens a new path forward in the field of radiopharmaceuticals. We look forward to advancing this promising product candidate through therapeutic clinical studies."